COMPARATIVE-STUDIES OF PHENOTHIAZINE-DERIVATIVES FOR THEIR EFFECTS ONSWELLING OF NORMAL AND SICKLE ERYTHROCYTES

1. Three phenothiazines with similar structure; chlorpromazine (CPZ), triflupromazine (TFPZ), and trifluoperazine (TFP), were compared for t he potency of swelling of normal red cells and antisickling effect of red cell from patients with sickle cell disease. 2. Normal erythrocyte s treated with the phenothiazines became swollen within 60 min, and th e percent increase in mean cell volume (MCV) was dose-dependent and va ried according to the agent used. 3. The cell swelling was hematocrit- dependent, and pH-dependent. A greater swelling potency was seen at lo wer hematocrits and higher pH values. 4. The swelling was also depende nt on the pK(a) values of these chemicals. TFP with the lowest pK(a) i nduced the highest degree of swelling while CPZ with the highest pK(a) induced the lowest. 5. The un-ionized fraction of the phenothiazines at a given pH was directly related to potency of the swelling. 6. The cell swelling was directly related to the binding affinities of the ph enothiazines to calmodulin. 7. The antisickling effect of these compou nds using sickle red cells, numerically estimated by an automated imag e analysis system, was found in the same order as that of swelling pot ency: TFP > TFPR > CPZ.